Coffee break has no impact on laparoscopic skills: a randomized double-blinded placebo-controlled parallel-group trial.

BACKGROUND: Coffee is a widely consumed beverage. Surgeons often drink coffee before performing surgery. Caffeine intake leads to tremor which might have a negative effect on surgeons' fine motor skills. METHODS: A double-blinded parallel-group trial was conducted in order to investigate if caffeinated coffee intake has a negative effect on laparoscopic skills and increases tremor, regardless of previous coffee consumption. 118 participants were selected during a congress of the German Society of Surgery. Exclusion criteria were immaturity and no given consent. Participants and investigators were blinded. Participants were randomized with a 1:1 allocation into interventional group receiving caffeinated coffee or placebo group receiving decaffeinated coffee. The motor skills were tested with two validated laparoscopic exercises at a laparoscopy simulator (LapSim®) before and 30 min after coffee intake. Data on influencing factors were recorded in a standardized questionnaire and tested for equal distribution in both groups. In both exercises four parameters were recorded: left and right hand path length and angular path. Their differences and the resulting effect scores were calculated for both groups as primary outcome to test which group showed greater improvement on the second round of exercises. Registration number DRKS00023608, registered retrospectively. RESULTS: Fifty nine subjects were assigned to each the interventional (54 analyzed) and placebo group (53 analyzed) with 11 drop outs. There was no significant difference between the placebo and interventional group in the two exercises in effect score 30 min after coffee intake [mean (SD); 38.58 (10.66) vs. 41.73 (7.40) and 113.09 (28.94) vs. 116.59 (25.63)]. A significant improvement from first to second measurement in the first exercise could be observed for both groups, demonstrating the training effect. CONCLUSION: In our study, we verified that additional caffeinated coffee intake, e.g., during a coffee break, does not lead to deterioration of laparoscopic fine motor skills.

Anxiety, Depression and Quality of Life in Patients with Neuroendocrine Neoplasia After Surgery.

BACKGROUND: Neuroendocrine neoplasia (NEN) are rare and complex, with surgery as key therapy even in cases with metastasis. Little is known regarding the quality of life, prevalence of depression, anxiety and the impact of surgery. METHODS: This prospective, follow-up study included 90 consecutively recruited patients with NEN after surgery in a university hospital. The EORTC QLQ-C30, EORTC QLQ-GI-NET.21, and Hospital Anxiety and Depression Scale and a hospital specific questionnaire were completed during follow-up after 3 to 5 years (t1-t5). RESULTS: Mean age was 54 (SD 15) years, 13% had secondary malignancies and 11% had psychiatric diagnoses (depression n = 8, schizophrenia n = 2) pre-existent. Critical life events occurred in 51% within 5 years before diagnosis. Surgery was done in curative intention in 82% and R0-resection rate was 90%. The median survival was 25.3 years. The 10-year survival rate was 87%, 98%, 95% and 26% for all patients (n = 90), stage I/II (n = 45), stage III (n = 25) and stage IV (n = 20), respectively (p < .001). Anxiety score was pathological in 30% after 1 year (t1) and in 10% after 5 years, depression score in 25% (t1) and 30% (t5). Fatigue and muscle/body pain were elevated symptoms with > 50 and 40 points 3 years after surgery. CONCLUSION: Depression rate remains high whereas anxiety declines over time. Fatigue and muscle/body pain were identified as relevantly elevated after surgery. Systematic screening and supportive therapy should be implemented during follow-up after surgery.

[Endoscopic Interventional Treatment of Precancerous Lesions and Early Carcinoma of the Esophagus - Criteria and Techniques of Local Ablation and Resection]. / Endoskopisch interventionelle Behandlung von Malignitätsvorstufen und des Frühkarzinomes des Ösophagus.

Endoscopic Interventional Treatment of Precancerous Lesions and Early Carcinoma of the Esophagus - Criteria and Techniques of Local Ablation and Resection Abstract. Early carcinomas of the esophagus can safely be resected endoscopically and interventionally under very strict conditions (ER). In contrast to ablative procedures (radiofrequency ablation, cryo-ablation, argon plasma coagulation, photodynamic therapy), which can only be recommended for Barrett's or low-grade dysplasia, ER - which is called EMR (endoscopic mucosal resection in adenocarcinoma) or more in-depth ESD (endoscopic submucosa dissection in squamous cell carcinoma) - a defined, histologically examinable preparation. This is required starting with high-grade dysplasia, since 50% of patients with biopsy-confirmed high-grade dysplasia after ER already have an invasive carcinoma in the specimen. This diagnostic gap is thus also closed with an interventional ER. ER is therefore an option for high-grade dysplasia in Barrett's, carcinoma in situ (Cis) and conditionally in T1a (adeno- and squamous cell carcinoma) and early T1b tumors (adenocarcinoma).

[Achalasia Update]. / Update Achalasie.

Achalasia Update Abstract. The neurodegenerative disease achalasia (obsolete: "cardiac spasm") is the second most common functional disease of the esophagus after reflux disease. It is associated with an extremely high level of suffering for the patient. Pathophysiologically, it is a combination of a lack of swallowing-reflex relaxation at the gastric entrance and disturbed peristalsis of the tubular esophagus. The gold standard in diagnostics is high-resolution manometry. The disease cannot be cured, the therapeutic spectrum that alleviates the disease includes pharmaceutical, endoscopic-interventional and surgical procedures.

[Complications and Management of Complications After Resection and Reconstruction of the Esophagus]. / Komplikationen und Komplikationsmanagement nach Resektion und Rekonstruktion der Speiseröhre.

Complications and Management of Complications After Resection and Reconstruction of the Esophagus Abstract. A curative therapy of advanced esophagus carcinoma is primarily made possible by radical esophagectomy with lymphadenectomy. Impressive advances in the surgical techniques of esophageal surgery through minimally invasive and robotic oesophagectomy have been made in the last two decades. The perioperative management with prehabilitation, PDK application, early mobilization and early food intake also contributed significantly to a reduction in complications. However, esophageal surgery is fraught with complications. Anastomotic leakage is the most common technical-surgical complication. The rate is approximately 10-16%, independent of the technique and procedure. In addition to an experienced, subtle, atraumatic and rapid surgical technique, early detection (clinical, endoscopic, radiological) and adequate, interdisciplinary management of perioperative complications in resecting esophageal surgery are the key to increasing the safety of these complex interventions. The treatment of the complications includes conservative, interventional and surgical measures. In the last few decades, there has been a radical change from once exclusively surgical revisions with a high degree of invasiveness and a poor outcome to today's mostly conservative-interventional management with little patient burden and - in centers with the appropriate expertise - good results.

[Curative Treatment of Esophageal Carcinoma - Disease, Diagnostics, Therapy in 2022]. / Kurative Therapie des Ösophaguskarzinomes.

Curative Treatment of Esophageal Carcinoma - Disease, Diagnostics, Therapy in 2022 Abstract. Surgical resection remains the gold standard for non-metastatic carcinoma of the lower and middle third of the esophagus. Locally advanced tumors (T3) are pretreated neoadjuvantly (radiochemotherapy) or perioperatively (chemotherapy). A differentiated primary staging and an interdisciplinary case presentation are of essential importance today. The individual risk assessment, the pre-habilitation and the individualized treatment play a major role. Clinically, the further advancement of access minimization - through laparoscopic/thoracoscopic and robot-assisted procedures and the associated reduction of access trauma - as well as the treatment of this entity in high volume centers are clearly in the foreground. For cervical carcinomas definitive radiotherapy is often the better alternative, both for tumor biological reasons and for reasons of the increase in complications during surgery.

[Results of pancreatic surgery from the perspective of patients: a cross-sectional study of the support group "Arbeitskreis der Pankreatektomierten e. V."] / Ergebnisse nach Pankreaseingriffen aus Sicht der Betroffenen: Versorgungsforschung der Selbsthilfegruppe "Arbeitskreis der Pankreatektomierten e. V.".

BACKGROUND: The support group "Arbeitskreis der Pankreatektomierten e. V. (AdP)" was founded in 1976 and is the largest group of individuals affected by pancreatic disease in Germany. Members of the AdP support patients with pancreatic disease. This patient-initiated, cross-sectional study intends to present the results of pancreatic surgery from the perspective of patients. METHODS: Since March the 3 rd, 2018, members of the AdP received a questionnaire with eleven categories of questions concerning their medical history. This data was gathered in a medical database and analysed. RESULTS: 625 members were operated upon, with 57.5 % receiving pancreaticoduodenectomy, 15.5 % distal pancreatectomy, 23.2 % total pancreatectomy, and 4.0 % another or unknown operation. 37.9 % were diagnosed with pancreatic cancer, 38.2 % with another type of pancreatic tumour, 25 % with pancreatitis, 4 % with autoimmune pancreatitis and 2.7 % with other rare entities.82 patients of 237 pancreatic cancer patients survived more than 5 years. 24.5 % of the 237 patients reported have a second primary malignancy and 13.9 % have close family members with pancreatic cancer.Weight loss after pancreatic surgery was dependant on the type of operation with the greatest after pancreatectomy (17.8 ±â€Š9.5 kg). The prevalence of diabetes was 54.1 %, the incidence of new onset perioperative diabetes 33.3 %. 91.5 % needed pancreatic enzyme replacement therapy, on average 189 417 IE/day. The reported quality of life was independent from type of surgery received. CONCLUSION: Following complex pancreatic surgery, patients are confronted with daily lifelong challenges. AdP members offering their shared experiences offer meaningful support to newly affected patients. Individuals affected by pancreatic disease could be an important but underutilised resource to studying these diseases.

Photon Counting Computed Tomography in Rectal Cancer: Associations Between Iodine Concentration, Histopathology and Treatment Response: A Pilot Study.

RATIONALE AND OBJECTIVES: Common computed tomography (CT) investigation plays a limited role in characterizing and assessing the response of rectal cancer (RC) to neoadjuvant radiochemotherapy (NARC). Photon counting computed tomography (PCCT) improves the imaging quality and can provide multiparametric spectral image information including iodine concentration (IC). Our purpose was to analyze associations between IC and histopathology in RC and to evaluate the role of IC in response prediction to NARC. MATERIALS AND METHODS: Overall, 41 patients were included into the study, 14 women and 27 men, mean age, 65.5 years. PCCT in a portal venous phase of the abdomen was performed. In every case, a polygonal region of interest (ROI) was manually drawn on iodine maps. Normalized IC (NIC) was also calculated. Tumor stage, grade, lymphovascular invasion, circumferential resection margin, and tumor markers were analyzed. Tumor regression grade (absence/presence of tumor cells) after NARC was analyzed. NIC values in groups were compared to Mann-Whitney-U tests. Sensitivity, specificity, and area under the curve values were calculated. Intraclass correlation coefficient (ICC) was calculated. RESULTS: ICC was 0.93, 95%CI= (0.88; 0.96). Tumors with lymphovascular invasion showed higher NIC values in comparison to those without (p = 0.04). Tumors with response grade 2-4 showed higher pretreatment NIC values in comparison to lesions with response grade 0-1 (p = 0.01). A NIC value of 0.36 and higher can predict response grade 2-4 (sensitivity, 73.9%; specificity, 91.7%; area under the curve, 0.85). CONCLUSION: NIC values showed an excellent interreader agreement in RC. NIC can predict treatment response to NARC.

Pancreatic cancer in photon-counting CT: Low keV virtual monoenergetic images improve tumor conspicuity.

PURPOSE OF THE STUDY: The aim of the study was to identify differences in the tumor conspicuity of pancreatic adenocarcinomas in different monoenergetic or polyenergetic reconstructions and contrast phases in photon-counting CT (PCCT). MATERIAL AND METHODS: 34 patients were retrospectively enrolled in this study. Quantitative image analysis was performed with region of interest (ROI) measurements in different monoenergetic levels ranging from 40 up to 70 keV (5-point steps) and polyenergetic series. Tumor-parenchyma attenuation differences and contrast-to-noise-ratio (CNR) were calculated. A qualitative image analysis was accomplished by 4 radiologists using a 5-point Likert scale (1 = "not recognizable" up to 5 = "easy recognizable"). Differences between groups were evaluated for statistical significance using the Friedman test and in case of significant differences pair-wise post-hoc testing with Bonferroni correction was applied. RESULTS: Tumor-parenchyma attenuation difference was significantly different between the different image reconstructions for both arterial- and portal-venous-phase-images (p < 0.001). Tumor-parenchyma attenuation difference was significantly higher on arterial-phase-images at mono40keV compared to polyenergetic images (p < 0.001) and mono55keV images or higher (p < 0.001). For portal-venous-phase-images tumor-parenchyma attenuation difference was significantly higher on mono40keV images compared to polyenergetic images (p < 0.001) and mono50keV images (p = 0.03) or higher (p < 0.001). The same trend was seen for CNR. Tumor conspicuity was rated best on mono40keV images with 4.3 ± 0.9 for arterial-phase-images and 4.3 ± 1.1 for portal-venous-phase-images. In contrast, overall image quality was rated best on polyenergetic-images with 4.8 ± 0.5 for arterial-phase-images and 4.7 ± 0.6 for portal-venous-phase-images. CONCLUSION: Low keV virtual monoenergetic images significantly improve the tumor conspicuity of pancreatic adenocarcinomas in PCCT based on quantitative and qualitative results. On the other hand, readers prefer polyenergetic images for overall image quality.

[Simulation of laparoscopic surgery--four years' experience at the Department of Surgery of the University Hospital Marburg]. / Simulation endoskopischer Operationen - Vier Jahre Erfahrung an der Chirurgischen Universitätsklinik Marburg.

It is well known that learning curves are longer for laparoscopic surgery compared to open surgery. Recently, virtual reality (VR) simulation was developed as alternative to conventional training. Such a new training system makes it possible to offer a wide range of repeatable surgical situations, and thus, enable assessments based on direct observation of performance. During the last four years we did several studies using a VR simulator (LapSim). After a constructive validity study - discrimination between novices and experienced laparoscopic surgeons, we were able to show that advanced residents benefit most from a three-day practical course for laparoscopic surgery, while - in a further investigation - we found contrary to training at the Pelvitrainer that novices in laparoscopic surgery have the most benefit from VR training. Minimally invasive surgery is significantly more sophisticated for the surgeon than open surgery. While Research on laparoscopic surgery has focused primarily on the development and assessment of technical skills, non technical skills such as visual-spatial perception and stress coping has received much less attention. We showed that spatial perception as well as stress coping positively correlates with virtual laparoscopic skills. A high degree of spatial perception led to faster adaption to a non-stereo environment and correlated with high level of laparoscopic skills. Furthermore, Ineffective stress-coping strategies correlate with poor virtual laparoscopic performance. VR simulation seems to be a promising tool to improve laparoscopic skills in a modern apprenticeship model. According to patient safety, the development of this instrument for surgery should be advanced professionally just as a flight simulators in aviation.

Improvement of surgical skills after a three-day practical course for laparoscopic surgery.

OBJECTIVES: Currently, skills labs are becoming increasingly important in the field of medical education. This study aims to objectively assess psychomotor skills acquisition of residents attending a three-day laparoscopic course. MATERIALS AND METHODS: 44 participants (test group) of the sixth practical course for Visceral Surgery of German surgical societies (Deutsche Gesellschaft für Chirurgie; DGCH and Berufsverband Deutscher Chirurgen; BDC) in Warnemuende with various degree of experience in laparoscopic surgery (18 advanced residents performing more than 50 laparoscopic operations and 26 novices performing less than 10 laparoscopic operations) and 6 consultants attending as tutors of the course (gold standard) were recruited as subjects. 20 medical students in their final year (camera holder) were chosen as a second control group (naive). Both control groups had no training during the practical course. The virtual reality simulator LapSim was used to assess laparoscopic skills of participants before and after the course. Time to complete the tasks, error score, and economy of motion parameters (path length and angular path) were analysed. RESULTS: After the practical course the advanced participants of the test group completed the task significantly faster (p = 0.019), with smaller error score (p = 0.023), and more economy of motion [path length (p = 0.014) and angular path (p = 0.049)] than before the course. The novices of the test group and both control groups showed no significant improvement of their performance parameters (p >0.05). CONCLUSION: A three-day practical course for laparoscopic surgery improved laparoscopic skills of residents. However, advanced residents benefit most from the course.

BRCA2 germline mutations in familial pancreatic carcinoma.

BACKGROUND: Although as many as 10% of pancreatic cancer cases may have an inherited component, familial pancreatic cancer has not been linked to defects in any specific gene. Some studies have shown that families with germline mutations in the breast cancer susceptibility gene BRCA2 have an increased risk of breast and ovarian cancers, as well as a modestly increased risk of pancreatic cancer. To study these relationships in more detail, we examined whether BRCA2 germline mutations are associated with familial pancreatic cancer. METHODS: We identified 26 European families in which at least two first-degree relatives had a histologically confirmed diagnosis of pancreatic ductal adenocarcinoma. We sequenced genomic DNA isolated from peripheral blood lymphocytes obtained from participating family members to identify germline mutations in BRCA2. RESULTS: Three (12%, exact 95% confidence interval [CI] = 2% to 30%) families carried germline frameshift mutations in the BRCA2 gene that are predicted to result in a truncated BRCA2 protein. Two additional families harbored mutations previously designated as unclassified variants of BRCA2. Thus, 19% (exact 95% CI = 7% to 39%) of the families in our study had either a frameshift mutation or an unclassified variant of BRCA2. None of the families in our study met the criteria for familial breast or ovarian cancer. CONCLUSIONS: Our data support an important role for BRCA2 germline mutations in a subpopulation of families with familial pancreatic cancer. BRCA2 mutation analysis should be included in molecular genetic testing and counseling strategies in families with at least two first-degree relatives affected with ductal adenocarcinoma of the pancreas.

Incarceration of Meckel's diverticulum in a left paraduodenal Treitz' hernia.

Meckel's diverticula incarcerated in a hernia were first described anecdotally by Littré, a French surgeon, in 1700. Meckel, a German anatomist and surgeon, explained the pathophysiology of this disease 100 years later. In addition, a congenital paraduodenal mesocolic hernia, known as a Treitz hernia, is a rare cause of small bowel obstruction. These hernias are caused by an abnormal rotation of the primitive midgut, resulting in a right or left paraduodenal hernia. We treated a patient presenting with pain and diagnosed extraluminal air in the abdomen after a computed tomography examination. We performed a laparotomy and found a combination of these two seldomly occurring congenital diseases, incarceration and perforation of Meckel's diverticulum in a left paraduodenal hernia. We performed a thorough review of the literature, and this report is the first to describe a patient with a combination of these two rare conditions. We considered the case regarding the variety of terminology as well as the treatment options of these conditions.

[Familial pancreatic cancer--concept for study of the National Case Collection and early diagnosis program for high risk people]. / Familiäres Pankreaskarzinom--Studienkonzept einer Nationalen Fallsammlung mit Früherkennungsprogramm für Hochrisikopersonen.

Ductal pancreatic cancer is a public health problem on the increase. The lethality and incidence of this disease are almost identical. A number of these cancers cluster in families. By definition, pancreatic cancer appearing in at least two first degree relatives is named familial pancreatic cancer (FPC). The "National Case Collection Familial Pancreatic Cancer" (FaPaCa) was founded at the Philipps University of Marburg, Germany, in July 1999 within the scope of the project "Clinical and genetic examinations of familial exocrine pancreatic cancer including the foundation of a national case collection" (http://www.med.uni-marburg.de/fapaca). The aims of this project are 1 to evaluate the share of FPC of all pancreatic cancers by performing a multi-centered study, 2 to identify epidemiological risk factors that predispose to pancreatic cancer in these families, 3 to identify families with a likely genetic predisposition to pancreatic cancer, 4 to offer a screening program for high risk individuals in these families, which is to be evaluated in an observational study, and finally to identify presumed genetic defects that predispose to pancreatic cancer in FPC families. This manuscript presents the scientific concept behind the FaPaCa project and reports on its attendant screening program for FPC families.

Multiple primary malignancies in patients with sporadic pancreatic endocrine tumors.

BACKGROUND: To investigate the appearance of multiple primary malignancies in patients with sporadic neuroendocrine pancreatic tumors (NEPTs). METHODS: One hundred forty-five patients with NEPTs were treated at the Department of Surgery, Philipps-University Marburg. Multiple primary malignancies included tumors that were not considered to be a metastasis, invasion, or recurrence of NEPTs. Data on sex, age at diagnosis of cancer, follow-up time after diagnosis, and death rate were collected. RESULTS: Of 115 patients with sporadic NEPTs, 15 (13.0%) patients were identified with at least one malignant tumor, other than a NEPT. The median age at diagnosis of the associated tumor(s) was 57 years (range, 10-72 years). Two of the 15 patients had insulinomas, 5 had gastrinomas and 8 had non-functioning NEPTs, respectively. The risk of developing multiple cancers was the highest for patients with gastrinoma (21.7%), followed by patients with non-functioning NFPTs (20.5%). CONCLUSIONS: In patients with NEPTs multiple primary malignancies are found more frequently than in the general population. The etiology of the increased risk of other primaries is not clearly defined, but it may be the result of accumulated growth stimulation by the secreted hormones or a genetic alteration that leads to tumorogenesis in these patients.

Novices in surgery are the target group of a virtual reality training laboratory.

BACKGROUND: This study aims to establish which physicians represent the suitable target group of a virtual training laboratory. METHODS: Novices (48 physicians with fewer than 10 laparoscopic operations) and intermediate trainees (19 physicians who performed 30-50 laparoscopic operations) participated in this study. Each participant performed the basic module 'clip application' at the beginning and after a 1-hour short training course on the LapSim. The course consisted of the tasks coordination, lift and grasp, clip application, cutting with diathermy and fine dissection at increasing difficulty levels. The time taken to complete the tasks, number of errors, and economy of motion parameters (path length and angular path) were analyzed. RESULTS: Following training with the simulator, novices completed the task significantly faster (p = 0.001), demonstrated a greater economy of motion [path length (p = 0.04) and angular path (p = 0.01)]. In contrast, the intermediate trainees showed a reduction of their errors, but without reaching statistical significance. They showed no improvement in economy of motion and completed the task significantly slower (p = 0.03). CONCLUSION: Novices, in comparison to intermediate trainees, tend to benefit most during their first exposure to a laparoscopy simulator.

Peripyloric lymph node metastasis is a rare condition in carcinoma of the pancreatic head.

OBJECTIVES: Pylorus preserving pancreatoduodenectomy (PPPD) was introduced to achieve a better functional result compared with the conventional Kausch-Whipple procedure (PD). In PPPD, peripyloric and perigastric lymphatic tissue is not removed compared with PD. The aim of this prospective study was to identify the frequency of peripyloric and perigastric lymph node metastases in ductal adenocarcinoma of the pancreatic head (PC). METHODS: Fifty specimens following Kausch-Whipple procedure including partial gastric resection for PC were analyzed for peripyloric and perigastric lymph node metastases by a standardized clearing technique. All lymph nodes of the specimens were counted, discriminating between those not removed ("group A") and those removed ("group B") in pylorus preserving resection of the pancreatic head. Additionally, the duodenal wall and paraduodenal tissue at a potential duodenal resection margin 2 cm distal of the pylorus were investigated histologically. RESULTS: Three of the 50 specimens (6%) carried peripyloric lymph node metastases, whereas 32 of the 50 specimens (64%) contained lymph node metastases in total. Four of 362 group A and 90 of 748 group B lymph nodes showed metastatic spread of the carcinoma. The 4 lymph node metastases in group A could be identified exclusively in 88 peripyloric lymph nodes but in none of the 274 perigastric lymph nodes at the lesser or greater curvature. In 2 of the 3 patients with peripyloric lymph node metastases, these lymph nodes were the only lymph nodes with metastatic involvement in the entire specimen. In 1 specimen, a small tumor nest of less than 2 mm in diameter was detected at a distance of less than 1 mm to the pylorus, although pyloric involvement was not suspected intraoperatively. The potential PPPD resection margin of the duodenal wall was not infiltrated by intramural tumor spread in any specimen. CONCLUSION: In a minority of 6%, PC metastasizes in peripyloric lymph nodes. Lymph nodes of the lesser and greater curvature of the stomach are not involved in patients with PC. Thus, we conclude by the data of this prospective study that the limited benefits of the extended lymph node dissection in a conventional Kausch-Whipple resection are far outweighed by the disadvantages construed by this procedure.

Alterations of the tissue inhibitor of metalloproteinase-3 (TIMP3) gene in pancreatic adenocarcinomas.

OBJECTIVES: Tissue inhibitor of metalloproteinase-3 (TIMP3) antagonizes matrix metalloproteinase activity and can suppress tumor growth, angiogenesis, invasion, and metastases. In the present study, the involvement of TIMP3 in the tumorigenesis of 34 pancreatic adenocarcinomas was evaluated. METHODS: Immunohistochemistry, methylation-specific PCR, and RNA expression analysis (RT-PCR) of TIMP3 were performed in 34 resected and microdissected primary pancreatic adenocarcinomas. RESULTS: Immunohistochemistry showed loss or strongly reduced protein expression in 17 of 34 pancreatic adenocarcinomas (50%) that corresponded to loss of TIMP3-RNA-expression. Promoter hypermethylation was identified in 2 of 34 tumors (6%). It was tumor specific and corresponded to a loss of TIMP3 protein expression. TIMP3 alterations did not correlate with any clinical feature such as tumor size or survival. CONCLUSION: TIMP3 seems to play an important role in the tumorigenesis of primary pancreatic adenocarcinomas. In contrast to other tumors, hypermethylation seems not to be the key mechanism for the inactivation of TIMP3. Other methods of gene inactivation need to be identified.

p16INK4a is a prognostic marker in resected ductal pancreatic cancer: an analysis of p16INK4a, p53, MDM2, an Rb.

OBJECTIVE: To identify the prognostic relevance of the G1/S cell cycle regulator genes p16INK4a, p53, MDM2, and Rb in patients with resected ductal pancreatic cancer (PC). SUMMARY BACKGROUND DATA: The tumor suppressor genes p16INK4a, p53, and Rb are altered in PC in 27% to 95%, 40% to 70%, and 5%, respectively. The role of MDM2 is not clearly defined in PC. The prognostic value of these cell cycle regulators has not been clarified. METHODS: Sixty-two patients with PC with complete follow-up who underwent potentially curative resections were included in the study. An extreme group analysis was performed including the 20 patients with the shortest survival and the 20 patients with the longest survival. Protein expression of p16, p53, MDM2, and Rb was investigated, and mutation analysis of p16INK4a and p53 was performed. p16INK4a promoter hypermethylation was examined by methylation-specific polymerase chain reaction. RESULTS: Significantly more tumors in the shortest-surviving patients had p16INK4a alterations compared with tumors of the longest-surviving patients. In contrast, the frequency of p53 alterations was not significantly higher in the shortest-surviving versus the longest-surviving groups. Stabilization of MDM2 and loss of Rb expression were identified in a minority of tumors, independent of survival length. CONCLUSIONS: The presence of p16INK4a alterations in resected tumors of patients with PC is connected with a worse prognosis, indicating patients that might benefit from adjuvant therapy regimens. p53 alterations, MDM2 overexpression, and loss of Rb expression could not be identified as prognostic markers from this study, but a larger study with greater statistical power might show a different result with regard to p53.